LIPID ABNORMALITIES IN TISSUES OF THE KKA(Y) MOUSE - EFFECTS OF PIOGLITAZONE ON MALONYL-COA AND DIACYLGLYCEROL

Insulin resistance is present in liver and muscle of subjects with type 2 diabetes and obesity. Recent studies suggest that such insulin resistance could be related to abnormalities in lipid-mediated signal transduction; however, the nature of these abnormalities is unclear. To examine this question further, tissue levels of diacylglycerol (DAG), malonyl-CoA, and triglyceride (TG) were determined in liver and soleus muscle of obese insulin-resistant KKA(y) mice and lean C57 BL control mice. In addition, the effects of treatment with pioglitazone, an antidiabetic agent that acts by increasing insulin sensitivity in muscle, liver, and other tissues, were assessed. The KKA(y) mice were hyperglycemic (407 vs. 138 mg/dl), hypertriglyceridemic (337 vs. 109 mg/dl), hyperinsulinemic (631 vs. 15 mU/ml), and weighed more (42 vs. 35 g) than the control mice. They also had 1.5- to 2.0-fold higher levels of malonyl-CoA in both liver and muscle, higher DAG (twofold) and TG (1.3-fold) levels in muscle, and higher TG (threefold), but not DAG, levels in liver. Treatment of the KKA(y) mice with pioglitazone for 4 days decreased plasma glucose, TGs, and insulin by similar to 50% and restored hepatic and muscle malonyl-CoA levels to control values. In contrast, pioglitazone increased hepatic and muscle DAG levels two- or threefold. It had no effect on muscle or hepatic TG content, and it slightly increased hepatic TGs in the control group. The results indicate that abnormalities in tissue lipids occur in both liver and muscle of the KKA(y) mouse and that they are differentially altered when insulin sensitivity is enhanced by treatment with pioglitazone. Improved insulin sensitivity correlated most closely with reduction in the content of malonyl-CoA, suggesting a possible link between the cytosolic concentration of long chain fatty acyl-CoA and insulin action.